Pharmacokinetic interaction between fimasartan and atorvastatin in healthy male volunteers

Choi, Yewon; Lee, Seung Hwan; Jang, In Jin; Yu, Kyung‐Sang

doi:10.2147/dddt.s165171

Cited by 5 publications

(3 citation statements)

References 29 publications

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“…Additionally, atorvastatin increased exposure of fimasartan by 2.18-fold and 1.35fold for C max and AUC last , respectively. 12 However, considering the wide therapeutic range of fimasartan and atorvastatin 12,13 and that AUC is well correlated to the therapeutic effect rather than to the C max , the pharmacokinetic interaction between fimasartan and atorvastatin seems to be limited in terms of clinical outcome. Therefore, the combination of these two drugs is clinically common.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the Pharmacokinetics of Highly Variable Drugs in Healthy Subjects Using a Partial Replicated Crossover Study: A Fixed-Dose Combination of Fimasartan 120 mg and Atorvastatin 40 mg versus Separate Tablets

Hwang

Lee

2020

DDDT

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Purpose: A fixed-dose combination (FDC) of fimasartan and atorvastatin is used to treat hypertension and dyslipidemia. The peak plasma concentration (C max ) of fimasartan and atorvastatin has a large intra-subject variability with a maximum coefficient of variation of 65% and 48%, respectively. Therefore, both drugs are classified as highly variable drugs. The purpose of this study was to compare the pharmacokinetics (PK) between a FDC of fimasartan 120 mg and atorvastatin 40 mg versus separate tablets in healthy male Korean subjects. Subjects and Methods: A randomized, single-dose, two-treatment, three-sequence, threeperiod, partial replicated crossover study was conducted with a 7-day washout interval between periods. Blood samples for fimasartan and atorvastatin were collected until 48 hours after administration in each period. PK parameters were calculated using the noncompartmental method. Geometric mean ratios (GMRs) for PK parameters of FDC to loose combination and their 90% confidence intervals (90% CIs) were estimated. Results: A total of 56 subjects completed the study. GMRs (90% CIs) of the C max for fimasartan and atorvastatin were 1.08 (0.93-1.24) and 1.02 (0.92-1.13), respectively. The expanded 90% CIs of both drugs using the intra-subject variability was calculated range of 0.70-1.43 and 0.73-1.38, respectively. The corresponding values of area under the concentration-time curve from zero to the last measurable time point were 1.02 (0.97-1.08) and 1.02 (0.98-1.07), respectively. Conclusion: FDC of fimasartan 120 mg and atorvastatin 40 mg between their loose combination showed similar PK characteristics.

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Section: Introductionmentioning

confidence: 99%

Comparison of the Pharmacokinetics of Highly Variable Drugs in Healthy Subjects Using a Partial Replicated Crossover Study: A Fixed-Dose Combination of Fimasartan 120 mg and Atorvastatin 40 mg versus Separate Tablets

Hwang

Lee

2020

DDDT

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“…These findings indicate that fimasartan is a highly variable drug with large within-subject variability for C max (CV w ¼ 0:77) and moderate within-subject variance for AUC (CV w ¼ 0:27), similar to that reported in previous studies. 22,23 As shown in the tramadol data, the fimasartan data have strong positive correlations (r = 0.832) between subject random effects for log(C max ) and those for log(AUC 0-24 ) in Figure S1d. Therefore, there are differences between the results obtained using two separate LMMs and a bivariate HGLM.…”

Section: Fimasartan Datamentioning

confidence: 73%

Multivariate Assessment for Bioequivalence Based on the Correlation of Random Effect

An¹,

Shin²

2021

DDDT

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Background and Objective: Bioequivalence tests are fundamental step in assessing the equivalence in bioavailability between a test and reference product. In practice, two separate linear mixed models (LMMs) with random subject effects, which have an area under the concentration-time curve (AUC) and the peak concentration (C max ) as the responses, have become the gold standard for evaluating bioequivalence. Recently, Lee et al developed a multivariate hierarchical generalized linear model (HGLM) for several responses that modeled correlations among multivariate responses via correlated random effects. The objective of this study was to apply this multivariate analysis to the bioequivalence test in practice and to compare the performance of multivariate HGLM and separate LMMs. Methods: Three pharmacokinetic datasets, fixed-dose combination (naproxen and esomeprazole), tramadol and fimasartan data were analyzed. We compared the 90% confidence interval (CI) for the geometric mean ratio (GMR) of a test product to a reference product using the multivariate HGLM and two conventional separate LMMs. Results: We found that the 90% CIs for the GMRs of both AUC and C max from the multivariate HGLM were narrower than those from the separate LMMs: (0.843, 1.152) vs (0.825, 1.177) for C max of esomeprazole in fixed-dose combination data; (0.805, 0.931) vs (0.797, 0.941) for C max in tramadol data; (0.801, 1.501) vs (0.762, 1.578) for C max and (1.163, 1.332) vs (1.009, 1.341) for AUC in fimasartan data, consistent with the random subject effects from two separate LMMs being highly correlated in the three datasets (correlation coefficient r = 0.883; r = 0.966; r = 0.832). Conclusion:This multivariate HGLM had good performance in the bioequivalence test with multiple endpoints. This method would provide a more reasonable option to reduce the 90% CI by adding correlation parameters and thus an advantage especially in evaluating the bioequivalence of highly variable drugs with broad 90% CIs.

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“…Rosuvastatin, however, is not one of such statins. On the other hand, ARBs such as telmisartan rarely show significant interactions with CCBs or statins; only a few pharmacokinetic interactions between ARBs and statins had been reported, such as the one between fimasartan and atorvastatin 11,25,26. Although telmisartan/amlodipine was selected in our study because it was the best-selling antihypertensive combination in South Korea, further studies that investigate the pharmacokinetic interaction between ARBs, CCBs and statins may help in decision making process of developing new fixed dose combination.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic interactions between telmisartan/amlodipine and rosuvastatin after multiple oral administrations in healthy Korean male subjects

Moon¹,

Jeon²,

Jang³

et al. 2019

DDDT

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Purpose Hypertension and dyslipidemia are major risk factors for cardiovascular diseases, and reduction of cardiovascular risks can be achieved by combining antihypertensive therapy with statins. The objective of this study was to evaluate the pharmacokinetic interaction between telmisartan/amlodipine fixed dose combination and rosuvastatin in healthy Korean male volunteers. Patients and methods An open-label, two-cohort, multiple-dose, single-sequence crossover study was conducted in healthy male subjects. In Cohort 1, the subjects were administered one tablet of telmisartan/amlodipine 80 mg/5 mg once daily for 14 days with or without one tablet of rosuvastatin 20 mg once daily. In Cohort 2, the subjects were administered one tablet of rosuvastatin 20 mg once daily for 14 days with or without one tablet of telmisartan/amlodipine 80 mg/5 mg once daily. Serial blood samples were collected up to 24 hrs post-dose on the 9th and 14th days in Cohort 1 and on the 5th and 14th days in Cohort 2. Plasma drug concentrations were measured by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration at steady state (C max,ss ) and area under the plasma concentration versus time curve over dosing interval (AUC τ,ss ), were determined by non-compartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% confidence intervals (CIs) of log-transformed C max,ss and AUC τ,ss for separate or concurrent therapy were calculated to evaluate pharmacokinetic interactions. Results Thirty-eight subjects from Cohort 1 and nineteen subjects from Cohort 2 completed the study. The GLSM ratios and 90% CIs of C max,ss and AUC τ,ss, were 0.9829 (0.8334–1.1590) and 1.0003 (0.9342–1.0710) for telmisartan; 0.9908 (0.9602–1.0223) and 1.0081 (0.9758–1.0413) for amlodipine; and 2.2762 (2.0113–2.5758) and 1.3261 (1.2385–1.4198) for rosuvastatin, respectively. Conclusion The pharmacokinetic parameters of telmisartan/amlodipine, but not rosuvastatin, met the pharmacokinetic equivalent criteria. The increase in systemic exposure to rosuvastatin caused by telmisartan/amlodipine co-administration would not be clinically significant in practice. Nevertheless, an appropriately designed two-sequence crossover study is needed to confirm the results of this study.

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Pharmacokinetic interaction between fimasartan and atorvastatin in healthy male volunteers

Cited by 5 publications

References 29 publications

<p>Comparison of the Pharmacokinetics of Highly Variable Drugs in Healthy Subjects Using a Partial Replicated Crossover Study: A Fixed-Dose Combination of Fimasartan 120 mg and Atorvastatin 40 mg versus Separate Tablets</p>

<p>Comparison of the Pharmacokinetics of Highly Variable Drugs in Healthy Subjects Using a Partial Replicated Crossover Study: A Fixed-Dose Combination of Fimasartan 120 mg and Atorvastatin 40 mg versus Separate Tablets</p>

Multivariate Assessment for Bioequivalence Based on the Correlation of Random Effect

<p>Pharmacokinetic interactions between telmisartan/amlodipine and rosuvastatin after multiple oral administrations in healthy Korean male subjects</p>

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